Adrian Bracken
@adrianbracken.bsky.social
Epigenetics & Chromatin Biology | Polycombs in Development & Disease | Cancer Genetics | Professor of Chromatin Biology, Trinity College Dublin | www.brackenlab.com
Pinned
Adrian Bracken
@adrianbracken.bsky.social
· Oct 31
1/ 🚀 AEBP2 isn’t what we thought.
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
Reposted by Adrian Bracken
Just one week to go until Edith Heard will be joining us for the All-Ireland Chromatin Consortium webinar on 'The Epigenetic Dynamics of X Inactivation in Development and Disease' 🧬
Registration link: us06web.zoom.us/webinar/regi...
Registration link: us06web.zoom.us/webinar/regi...
February 6, 2026 at 11:07 AM
Just one week to go until Edith Heard will be joining us for the All-Ireland Chromatin Consortium webinar on 'The Epigenetic Dynamics of X Inactivation in Development and Disease' 🧬
Registration link: us06web.zoom.us/webinar/regi...
Registration link: us06web.zoom.us/webinar/regi...
Reposted by Adrian Bracken
@adrianbracken.bsky.social we are looking forward to your presentation at our #FusionEpigenetics meeting in Portugal this October!
Please share this with your followers to let them know you will speaking, and to register & submit today to join us
🔗 bit.ly/4rC6B45
Please share this with your followers to let them know you will speaking, and to register & submit today to join us
🔗 bit.ly/4rC6B45
February 4, 2026 at 3:56 PM
@adrianbracken.bsky.social we are looking forward to your presentation at our #FusionEpigenetics meeting in Portugal this October!
Please share this with your followers to let them know you will speaking, and to register & submit today to join us
🔗 bit.ly/4rC6B45
Please share this with your followers to let them know you will speaking, and to register & submit today to join us
🔗 bit.ly/4rC6B45
Reposted by Adrian Bracken
Synovial sarcoma is driven almost exclusively by a single oncofusion – SS18-SSX
For years, the assumptions on disease mechanisms were simple:
➡️ SS18-SSX works by hijacking SWI/SNF chromatin remodeling activity
Our new study shows that assumption was wrong 🧵👇
www.biorxiv.org/content/10.6...
For years, the assumptions on disease mechanisms were simple:
➡️ SS18-SSX works by hijacking SWI/SNF chromatin remodeling activity
Our new study shows that assumption was wrong 🧵👇
www.biorxiv.org/content/10.6...
SS18-SSX co-opts P300 to sustain oncogenic transcription independent of SWI/SNF activity
Synovial sarcoma is driven by the SS18-SSX fusion oncoprotein, which has been assumed to promote tumorigenesis through its incorporation into the SWI/SNF chromatin remodeling complexes. Accordingly, therapeutic efforts have focused on targeting SS18-SSX containing SWI/SNF assemblies, yet these approaches have produced limited clinical benefit. Here, we demonstrate that SS18-SSX sustains oncogenic transcription independent of SWI/SNF activity. Despite efficient degradation and dismantling of SWI/SNF complexes, fusion occupancy at target loci and associated gene expression programs remain largely intact. Instead, we identify the acetyltransferase P300 as an essential co-factor supporting SS18-SSX chromatin binding and transcriptional activation. Targeting P300 displaces the fusion from chromatin, suppresses its transcriptional output, compromising synovial sarcoma viability. Notably, dual PROTAC mediated degradation of P300 and SWI/SNF produces strong synergistic effects, broadly disrupting SS18-SSX localization and function. These findings redefine the mechanistic basis of synovial sarcoma and reveal a mechanistically anchored therapeutic strategy for targeting its core oncogenic driver. ### Competing Interest Statement C.R.V. has been a consultant for Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. S.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Hyku Therapeutics, C4 Therapeutics, Accent Therapeutics and Nimbus Therapeutics; and has received research support from Janssen and Syndax. N.O.C. is a co-founder, shareholder and management consultant for PhenoTherapeutics Ltd; and a shareholder in Amplia Therapeutics Ltd All other authors declare no financial interests UKRI, EP/X039633/1 Worldwide Cancer Research, https://ror.org/031tfbz57, 21-0271 Science Foundation Ireland, https://ror.org/0271asj38, 18/SIRG/5573
www.biorxiv.org
January 28, 2026 at 9:54 AM
Synovial sarcoma is driven almost exclusively by a single oncofusion – SS18-SSX
For years, the assumptions on disease mechanisms were simple:
➡️ SS18-SSX works by hijacking SWI/SNF chromatin remodeling activity
Our new study shows that assumption was wrong 🧵👇
www.biorxiv.org/content/10.6...
For years, the assumptions on disease mechanisms were simple:
➡️ SS18-SSX works by hijacking SWI/SNF chromatin remodeling activity
Our new study shows that assumption was wrong 🧵👇
www.biorxiv.org/content/10.6...
Reposted by Adrian Bracken
After a short break in our webinars we are delighted to be back up & running this month!
First up, on Jan 30th we will be joined by @lucas.farnunglab.com from @harvardmed.bsky.social 🔬
Shortly after, on Feb 13th we will be hosting @heardlab.bsky.social from @crick.ac.uk 🧬
Registration details 👇
First up, on Jan 30th we will be joined by @lucas.farnunglab.com from @harvardmed.bsky.social 🔬
Shortly after, on Feb 13th we will be hosting @heardlab.bsky.social from @crick.ac.uk 🧬
Registration details 👇
January 15, 2026 at 2:59 PM
After a short break in our webinars we are delighted to be back up & running this month!
First up, on Jan 30th we will be joined by @lucas.farnunglab.com from @harvardmed.bsky.social 🔬
Shortly after, on Feb 13th we will be hosting @heardlab.bsky.social from @crick.ac.uk 🧬
Registration details 👇
First up, on Jan 30th we will be joined by @lucas.farnunglab.com from @harvardmed.bsky.social 🔬
Shortly after, on Feb 13th we will be hosting @heardlab.bsky.social from @crick.ac.uk 🧬
Registration details 👇
Reposted by Adrian Bracken
Two alternative isoforms of PRC2 accessory subunit AEBP2 modulate developmental Polycomb functions in opposite ways - with broadly-expressed AEBP2L acting as an intrinsic inhibitor in somatic cells
@adrianbracken.bsky.social @davidovichlab.bsky.social and colleagues
www.embopress.org/doi/full/10....
@adrianbracken.bsky.social @davidovichlab.bsky.social and colleagues
www.embopress.org/doi/full/10....
November 4, 2025 at 12:51 PM
Two alternative isoforms of PRC2 accessory subunit AEBP2 modulate developmental Polycomb functions in opposite ways - with broadly-expressed AEBP2L acting as an intrinsic inhibitor in somatic cells
@adrianbracken.bsky.social @davidovichlab.bsky.social and colleagues
www.embopress.org/doi/full/10....
@adrianbracken.bsky.social @davidovichlab.bsky.social and colleagues
www.embopress.org/doi/full/10....
Reposted by Adrian Bracken
We are delighted that @genesdev.bsky.social have selected our (w/ @adrianbracken.bsky.social) Weaver syndrome paper artwork as the November cover! This piece was made by my incredibly talented niece, Gina 'Dna Vinci' Ronan.
@ucddublin.bsky.social @tcddublin.bsky.social @ucd-sbbs.bsky.social
@ucddublin.bsky.social @tcddublin.bsky.social @ucd-sbbs.bsky.social
🚨 NEW ISSUE ALERT!!! 🚨
New Outlook, Review and Research articles online now at Genes & Development.
Click on the link to learn more:
➡️ https://genesdev.cshlp.org/content/39/21-22.toc
New Outlook, Review and Research articles online now at Genes & Development.
Click on the link to learn more:
➡️ https://genesdev.cshlp.org/content/39/21-22.toc
November 3, 2025 at 6:18 PM
We are delighted that @genesdev.bsky.social have selected our (w/ @adrianbracken.bsky.social) Weaver syndrome paper artwork as the November cover! This piece was made by my incredibly talented niece, Gina 'Dna Vinci' Ronan.
@ucddublin.bsky.social @tcddublin.bsky.social @ucd-sbbs.bsky.social
@ucddublin.bsky.social @tcddublin.bsky.social @ucd-sbbs.bsky.social
Thanks KJ. You’re exactly right. Since AEBP2-L is the broadly expressed isoform, it needs to get more attention. Chen’s lab did a great job of figuring out how its disordered N-terminal region works. What’s also cool is that it binds to PRC2 without JARID2 in many somatic cell types
November 1, 2025 at 12:06 AM
Thanks KJ. You’re exactly right. Since AEBP2-L is the broadly expressed isoform, it needs to get more attention. Chen’s lab did a great job of figuring out how its disordered N-terminal region works. What’s also cool is that it binds to PRC2 without JARID2 in many somatic cell types
16/ 📖 Again, please check out the full paper here: surl.li/cgwqcq
Huge thanks again to all collaborators and co-authors who made this project possible! 🙏
Huge thanks again to all collaborators and co-authors who made this project possible! 🙏
October 31, 2025 at 10:53 AM
16/ 📖 Again, please check out the full paper here: surl.li/cgwqcq
Huge thanks again to all collaborators and co-authors who made this project possible! 🙏
Huge thanks again to all collaborators and co-authors who made this project possible! 🙏
15/ This work highlights how evolution created a regulatory switch within a single protein isoform to restrain PRC2 activity in somatic tissues — a major step toward understanding PRC2 regulation during development, but also has relevance in terms of PRC2 dysregulation in cancer surl.li/jkrdbt
October 31, 2025 at 10:53 AM
15/ This work highlights how evolution created a regulatory switch within a single protein isoform to restrain PRC2 activity in somatic tissues — a major step toward understanding PRC2 regulation during development, but also has relevance in terms of PRC2 dysregulation in cancer surl.li/jkrdbt
14/ 💡 Key insight: We found that AEBP2-L ⏸️ acts as a brake on PRC2 in somatic cells, whereas AEBP2-S ⚡ boosts PRC2, but is only present in very early development.
Since most studies focus on AEBP2-S, we feel it's time the broadly expressed AEBP2-L 👀 gets the attention it deserves!
Since most studies focus on AEBP2-S, we feel it's time the broadly expressed AEBP2-L 👀 gets the attention it deserves!
October 31, 2025 at 10:53 AM
14/ 💡 Key insight: We found that AEBP2-L ⏸️ acts as a brake on PRC2 in somatic cells, whereas AEBP2-S ⚡ boosts PRC2, but is only present in very early development.
Since most studies focus on AEBP2-S, we feel it's time the broadly expressed AEBP2-L 👀 gets the attention it deserves!
Since most studies focus on AEBP2-S, we feel it's time the broadly expressed AEBP2-L 👀 gets the attention it deserves!
13/ ⚙️ Mechanistically, AEBP2-L contains a mammalian-specific, disordered N-terminal region with acidic tracts that we find inhibit PRC2 binding to chromatin. Mutations that neutralize this region relieve inhibition and boost H3K27 methyltransferase activity:
October 31, 2025 at 10:53 AM
13/ ⚙️ Mechanistically, AEBP2-L contains a mammalian-specific, disordered N-terminal region with acidic tracts that we find inhibit PRC2 binding to chromatin. Mutations that neutralize this region relieve inhibition and boost H3K27 methyltransferase activity:
12/ Interestingly, across mouse & human tissues, AEBP2-L is the predominant isoform from early embryogenesis, and broadly expressed.
Strikingly, the AEBP2-S isoform, which most labs study, is barely expressed beyond very early development!! 🤯
Strikingly, the AEBP2-S isoform, which most labs study, is barely expressed beyond very early development!! 🤯
October 31, 2025 at 10:53 AM
12/ Interestingly, across mouse & human tissues, AEBP2-L is the predominant isoform from early embryogenesis, and broadly expressed.
Strikingly, the AEBP2-S isoform, which most labs study, is barely expressed beyond very early development!! 🤯
Strikingly, the AEBP2-S isoform, which most labs study, is barely expressed beyond very early development!! 🤯
11/ We next wished to explore PRC2 integrity in the absence of AEBP2 isoforms with @michielvermeulen.bsky.social. We found that while loss of either isoform reduced JARID2 incorporation, JARID2 can associate with PRC2.2 with either isoform or even without both
October 31, 2025 at 10:53 AM
11/ We next wished to explore PRC2 integrity in the absence of AEBP2 isoforms with @michielvermeulen.bsky.social. We found that while loss of either isoform reduced JARID2 incorporation, JARID2 can associate with PRC2.2 with either isoform or even without both
10/ Indeed, loss of AEBP2-S KO impaired repression of 398 genes normally silenced by PRC2 during differentiation, whereas loss of AEBP2-L did not cause any defect
October 31, 2025 at 10:53 AM
10/ Indeed, loss of AEBP2-S KO impaired repression of 398 genes normally silenced by PRC2 during differentiation, whereas loss of AEBP2-L did not cause any defect
9/ If AEBP2-L acts like a Trithorax group protein, could AEBP2-S act like a Polycomb group protein? 🤔 We examined the roles of both isoforms during naive-to-primed pluripotency differentiation, which we previously used to study JARID2 during differentiation pubmed.ncbi.nlm.nih.gov/37030288/
October 31, 2025 at 10:53 AM
9/ If AEBP2-L acts like a Trithorax group protein, could AEBP2-S act like a Polycomb group protein? 🤔 We examined the roles of both isoforms during naive-to-primed pluripotency differentiation, which we previously used to study JARID2 during differentiation pubmed.ncbi.nlm.nih.gov/37030288/
8/ Notably, complete loss of AEBP2 (both isoforms) was shown by Brockdorff & Cooper (2016) to produce a Trithorax phenotype in mice, accompanied by increased PRC2 and H3K27me3 at target genes ⬆️
pubmed.ncbi.nlm.nih.gov/27317809/
pubmed.ncbi.nlm.nih.gov/27317809/
October 31, 2025 at 10:53 AM
8/ Notably, complete loss of AEBP2 (both isoforms) was shown by Brockdorff & Cooper (2016) to produce a Trithorax phenotype in mice, accompanied by increased PRC2 and H3K27me3 at target genes ⬆️
pubmed.ncbi.nlm.nih.gov/27317809/
pubmed.ncbi.nlm.nih.gov/27317809/
7/ AEBP2-L acts like a Trithorax group protein! 😲 We found that loss of AEBP2-L, but not AEBP2-S, increases ⬆️ PRC2 binding and H3K27me3 deposition on PcG target genes, mirroring the effect of losing both isoforms
October 31, 2025 at 10:53 AM
7/ AEBP2-L acts like a Trithorax group protein! 😲 We found that loss of AEBP2-L, but not AEBP2-S, increases ⬆️ PRC2 binding and H3K27me3 deposition on PcG target genes, mirroring the effect of losing both isoforms
6/ Next, to avoid any potential overexpression issues, we used CRISPR 🧬✂️ to KO either the short, the long or both isoforms in mouse ESCs:
October 31, 2025 at 10:53 AM
6/ Next, to avoid any potential overexpression issues, we used CRISPR 🧬✂️ to KO either the short, the long or both isoforms in mouse ESCs:
5/ We then confirmed in cells that ectopically expressed AEBP2-L does not binds PcG target genes as well as AEBP2-S. Curiously, ectopic overexpression of AEBP2-L, but not AEBP2-S, reduced overall SUZ12 (PRC2) binding ⬇️⬆️
October 31, 2025 at 10:53 AM
5/ We then confirmed in cells that ectopically expressed AEBP2-L does not binds PcG target genes as well as AEBP2-S. Curiously, ectopic overexpression of AEBP2-L, but not AEBP2-S, reduced overall SUZ12 (PRC2) binding ⬇️⬆️
4/ 🔍We focused on AEBP2, a PRC2 accessory subunit with two isoforms: AEBP2-S (short) and AEBP2-L (long).
Strikingly, we found AEBP2-L inhibits DNA binding by PRC2, whereas AEBP2-S promotes it:
Strikingly, we found AEBP2-L inhibits DNA binding by PRC2, whereas AEBP2-S promotes it:
October 31, 2025 at 10:53 AM
4/ 🔍We focused on AEBP2, a PRC2 accessory subunit with two isoforms: AEBP2-S (short) and AEBP2-L (long).
Strikingly, we found AEBP2-L inhibits DNA binding by PRC2, whereas AEBP2-S promotes it:
Strikingly, we found AEBP2-L inhibits DNA binding by PRC2, whereas AEBP2-S promotes it:
3/ PRC2 is a chromatin repressor complex essential for development and deregulated in disease. While several accessory proteins enhance PRC2, no endogenous inhibitor in somatic cells had been identified — until now! ⚡️
October 31, 2025 at 10:53 AM
3/ PRC2 is a chromatin repressor complex essential for development and deregulated in disease. While several accessory proteins enhance PRC2, no endogenous inhibitor in somatic cells had been identified — until now! ⚡️
2/ 🧵🌍 Firstly, a huge thank you to first authors Marlena Mucha, Zhihao Lai, Nicholas McKenzie, Francesca Matra. This was a joint effort with @davidovichlab.bsky.social with wonderful collaborations with labs at Radboud, NKI, USC & Garvan Institute 🙏🧵
October 31, 2025 at 10:53 AM
2/ 🧵🌍 Firstly, a huge thank you to first authors Marlena Mucha, Zhihao Lai, Nicholas McKenzie, Francesca Matra. This was a joint effort with @davidovichlab.bsky.social with wonderful collaborations with labs at Radboud, NKI, USC & Garvan Institute 🙏🧵
1/ 🚀 AEBP2 isn’t what we thought.
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
October 31, 2025 at 10:53 AM
1/ 🚀 AEBP2 isn’t what we thought.
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
You were told that AEBP2 promotes PRC2 activity on chromatin.
We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.
👉 surl.li/cgwqcq
A thread 🧵
Reposted by Adrian Bracken
Absolutely delighted to share our preprint, using functional genomics to uncover a novel dependency in lymphoma that can overcome resistance to targeted therapy. Grateful to co-first author @jamesnolan.bsky.social and co-senior authors @conwayer1.bsky.social and @adrianbracken.bsky.social see👇
🧵1/Exciting news in cancer epigenetics! Our latest research, "AEBP2-Directed H3K27me2 Defines a Specific Vulnerability in EZH2-mutant Lymphoma", is now available on www.biorxiv.org/content/10.1.... Here's a thread summarizing our findings!👇
#CancerResearch #Epigenetics #Chromatin #Lymphoma
#CancerResearch #Epigenetics #Chromatin #Lymphoma
AEBP2-Directed H3K27me2 Defines a Specific Vulnerability in EZH2-mutant Lymphoma
The catalytic subunit of Polycomb Repressive Complex 2 (PRC2), EZH2, is recurrently mutated in 25% of diffuse large B-cell lymphomas (DLBCL), causing increased H3K27me3 and decreased H3K27me2 levels. ...
www.biorxiv.org
October 17, 2025 at 2:07 PM
Absolutely delighted to share our preprint, using functional genomics to uncover a novel dependency in lymphoma that can overcome resistance to targeted therapy. Grateful to co-first author @jamesnolan.bsky.social and co-senior authors @conwayer1.bsky.social and @adrianbracken.bsky.social see👇